chr16-50712175-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001370466.1(NOD2):c.2183C>T(p.Ala728Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00348 in 1,613,954 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0028 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0035 ( 9 hom. )

Consequence

NOD2
NM_001370466.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:7

Conservation

PhyloP100: 1.86

Variant links:

Genes affected

NOD2 (HGNC:5331): (nucleotide binding oligomerization domain containing 2) This gene is a member of the Nod1/Apaf-1 family and encodes a protein with two caspase recruitment (CARD) domains and six leucine-rich repeats (LRRs). The protein is primarily expressed in the peripheral blood leukocytes. It plays a role in the immune response to intracellular bacterial lipopolysaccharides (LPS) by recognizing the muramyl dipeptide (MDP) derived from them and activating the NFKB protein. Mutations in this gene have been associated with Crohn disease and Blau syndrome. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jun 2014]

NOD2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014914691).

BP6

Variant 16-50712175-C-T is Benign according to our data. Variant chr16-50712175-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 319462.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=6}. Variant chr16-50712175-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00285 (434/152388) while in subpopulation NFE AF= 0.00525 (357/68040). AF 95% confidence interval is 0.0048. There are 1 homozygotes in gnomad4. There are 197 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOD2	NM_001370466.1 link	c.2183C>T	p.Ala728Val	missense_variant	Exon 4 of 12	ENST00000647318.2	NP_001357395.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOD2	ENST00000647318.2 link	c.2183C>T	p.Ala728Val	missense_variant	Exon 4 of 12		NM_001370466.1	ENSP00000495993.1		Q9HC29-2

Frequencies

GnomAD3 genomes

AF:

0.00285

AC:

434

AN:

152270

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000651

Gnomad AMI

AF:

0.0198

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00525

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00245

AC:

615

AN:

250870

Hom.:

AF XY:

0.00220

AC XY:

299

AN XY:

135722

show subpopulations

Gnomad AFR exome

AF:

0.000679

Gnomad AMR exome

AF:

0.000810

Gnomad ASJ exome

AF:

0.00139

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00234

Gnomad NFE exome

AF:

0.00435

Gnomad OTH exome

AF:

0.00294

GnomAD4 exome

AF:

0.00354

AC:

5178

AN:

1461566

Hom.:

Cov.:

AF XY:

0.00344

AC XY:

2500

AN XY:

727096

show subpopulations

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.000894

Gnomad4 ASJ exome

AF:

0.00122

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00284

Gnomad4 NFE exome

AF:

0.00430

Gnomad4 OTH exome

AF:

0.00250

GnomAD4 genome

AF:

0.00285

AC:

434

AN:

152388

Hom.:

Cov.:

AF XY:

0.00264

AC XY:

197

AN XY:

74522

show subpopulations

Gnomad4 AFR

AF:

0.000649

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00104

Gnomad4 NFE

AF:

0.00525

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00448

Hom.:

Bravo

AF:

0.00269

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00465

AC:

ExAC

AF:

0.00231

AC:

280

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00425

EpiControl

AF:

0.00344

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NOD2: BP4, BS1 -

Jun 14, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 05, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22056582, 12115249, 32463623, 11385576, 28814775, 16485124, 20032092, 11875755, 16965521, 18640012, 28887115, 31760574, 28422189, 34440800, 34975878, 32222431, 33692434, 37080976, 25416713) -

Sep 18, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NOD2 c.2264C>T; p.Ala755Val variant (rs61747625) is reported in the literature in one individual with a periodic fever syndrome, in one individual with an autoinflammatory disorder, in several individuals with Crohn's disease or ulcerative colitis (Andreoletti 2017, Batlle-Maso 2020, Burillo-Sanz 2017, Hugot 2001, Lesage 2002), and three individuals with Blau syndrome (Parackova 2020, Rose 2015). The variant is also reported in ClinVar (Variation ID: 319462) and found in the non-Finnish European population with an allele frequency of 0.45% (579/128986 alleles including 1 homozygote) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.475). This variant has a population frequency incompatible with periodic fever disease and familial segregation study does not fully support its pathogenic role in Blau syndrome, although functional study indicates a gain-of-function of the p.Ala755Val variant (Parackova 2020). Due to conflicting information, the clinical significance of the p.Ala755Val variant is uncertain at this time.Andreoletti G et al. Exome Analysis of Rare and Common Variants within the NOD Signaling Pathway. Sci Rep. 2017 Apr 19;7:46454. PMID: 28422189. Batlle-Maso L et al. Genetic diagnosis of autoinflammatory disease patients using clinical exome sequencing. Eur J Med Genet. 2020 May;63(5):103920. PMID: 32222431. Burillo-Sanz et al. Mutational profile of rare variants in inflammasome-related genes in Behcet disease: A Next Generation Sequencing approach. Sci Rep. 2017 Aug 16;7(1):8453. PMID: 28814775. References: Andreoletti G et al. Exome Analysis of Rare and Common Variants within the NOD Signaling Pathway. Sci Rep. 2017 Apr 19;7:46454. PMID: 28422189. Batlle-Maso L et al. Genetic diagnosis of autoinflammatory disease patients using clinical exome sequencing. Eur J Med Genet. 2020 May;63(5):103920. PMID: 32222431. Burillo-Sanz et al. Mutational profile of rare variants in inflammasome-related genes in Behcet disease: A Next Generation Sequencing approach. Sci Rep. 2017 Aug 16;7(1):8453. PMID: 28814775. Hugot et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature. 2001 May 31;411(6837):599-603. PMID: 11385576. Lesage S et al. CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease. Am J Hum Genet. 2002 Apr;70(4):845-57. PMID: 11875755. Parackova Z et al. Mutual alteration of NOD2-associated Blau syndrome and IFN?R1 deficiency. J Clin Immunol. 2020 Jan;40(1):165-178. PMID: 31760574. Rose et al. Blau syndrome: cross-sectional data from a multicentre study of clinical, radiological and functional outcomes. Rheumatology (Oxford). 2015 Jun;54(6):1008-16. PMID: 25416713. -

Psoriatic arthritis, susceptibility to;C4310620:Yao syndrome;C5201146:Blau syndrome;CN260071:Inflammatory bowel disease 1

Uncertain:1

Aug 09, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NOD2 NM_022162.2 exon 4 p.Ala755Val (c.2264C>T):This variant has been reported in the literature in several individuals with a variety of autoimmune conditions including Crohn's disease, Behcet's and Blau syndrome (also reported as p.Ala728Val-Hugot 2001 PMID:11385576, Rose 2015 PMID:25416713, Andreoletti 2017 PMID:28422189, Burillo-Sanz 2017 PMID:28814775, Batle-Maso 2020 PMID:32222431, Parakova 2020 PMID:31760574). This variant is present in 0.5% (357/68048) of European alleles including 1 homozygote in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-50712175-C-T?dataset=gnomad_r3). This variant is present in ClinVar, with classifications ranging from variant of uncertain significance to likely benign (Variation ID:319462). Evolutionary conservation suggests that this variant may not impact the protein; computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Regional enteritis;C5201146:Blau syndrome

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autoinflammatory syndrome

Benign:1

May 01, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inflammatory bowel disease 1

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Blau syndrome

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

NOD2-related disorder

Benign:1

Jun 11, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.40

.;T

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.81

T;T

M_CAP

Pathogenic

0.41

MetaRNN

Benign

0.015

T;T

MetaSVM

Benign

-0.32

MutationAssessor

Uncertain

2.8

.;M

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.1

.;D

REVEL

Uncertain

0.47

Sift

Uncertain

0.0030

.;D

Sift4G

Pathogenic

0.0

.;D

Polyphen

1.0

D;D

Vest4

0.53

MVP

0.90

MPC

0.50

ClinPred

0.023

GERP RS

5.5

Varity_R

0.34

gMVP

0.56

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over